Millions of diabetics are forced to draw blood daily to determine their blood sugar levels. To alleviate the constant discomfort of these individuals, substantial effort has been expanded in the search for a non-invasive methodology to accurately determine blood glucose levels. Two patent applications, each assigned to Optiscan Biomedical Corporation of Alameda, Calif., have significantly advanced the state of the art of non-invasive blood glucose analysis. The methodology taught in U.S. patent application Ser. No. 08/820,378 is performed by the apparatus taught in U.S. patent application Ser. No. 08/816,723, and each of these references is herewith incorporated by reference.
By way of introduction, the methodology taught in U.S. patent application Ser. No. 08/820,378 is introduced as follows.
Any object at a temperature above absolute zero (-273.16 degrees Celsius) emits infrared energy. The energy density of such emissions is described by Planck's law and are often referred to as a blackbody curves. Theoretically, a body with emissivity 1.0 would exhibit this emission spectra according to Planck's Equation. Many objects have emissivities close to 1.0. Human tissue for instance has an emissivity of approximately 0.9 to 0.98. It is well known that infrared emissions from the human body obey Planck's law and yield a black body type emission spectra.
Although a human body may emit energy that follows Planck's Equation, Planck's Equation does not completely describe the sum total of all energy emitted from a human body for two reasons:
1. The layers of the tissue and body fluids are selectively absorptive to some wavelengths of infrared energy. Thus, layers of tissue and blood or other fluids may selectively absorb energy emitted by the deeper layers before that energy can reach the surface of the skin. PA1 2. There is a temperature gradient within a body, the deeper layers being warmer than the outer layers, which causes further deviation from the theoretical black body emissions. PA1 cooling an infrared transmissive mass; PA1 placing the infrared transmissive mass into a conductive heat transfer relationship with the tissue, thereby generating a transient temperature gradient in the tissue; PA1 detecting infrared emissions emanating from the tissue and passing through the infrared transmissive mass; PA1 providing output signals proportional to the detected infrared emissions; and PA1 sampling the output signals as the transient temperature gradient progresses into the tissue.
Whenever these two conditions exist naturally, or can be forced to exist, the inventors have determined that a composition-dependent absorption spectra can be constructed from proper analysis of the total energy emitted from the body. For heterogeneous bodies, composition may be depth dependent and conversely, absorption spectra generated from deeper layers can contain sufficient composition information to allow quantification of the concentrations of individual constituents at that depth into the tissue. This is possible when a temperature gradient either occurs or is induced in the body. The slope of the temperature gradient is such that the temperature is cooler at the surface of the body closer to an infrared detector than at a more distant location from the detector, typically deep within the body.
The invention taught in U.S. patent application Ser. No. 08/820,378 uses the natural temperature within the body as the source of the infrared emissions. As will be explained in more detail below, as these deep infrared emissions pass through layers of tissue that are at a lower temperature than the deeper emitting layer, they are selectively self absorbed. This selective self-absorption produces bands of reduced energy in the resulting emission spectra when the energy finally exits the material under study. The spectra containing the bands where energy has been self absorbed is called an absorption spectra.
The invention taught in U.S. patent application Ser. No. 08/816,723 employs cooling to promote "self-absorption" by letting the temperature gradient propagate to selected layers typically between 40 and 150 microns below the surface. When the temperature gradient has sufficiently propagated, the techniques presented therein can non-invasively deliver absorption spectra of the tissue, blood, and interstitial fluid containing glucose. The inventions incorporated by reference can deliver precise information about the composition of individual layers deep within a heterogeneous body of material by measuring the absorption spectra at different times as a temperature gradient propagates from the surface to deep within the material under test.
According to Ser. No. 08/820,378, there is provided a spectrometer for the non-invasive generation and capture of thermal gradient spectra from human or animal tissue. The spectrometer includes an infrared transmissive thermal mass for inducing a transient temperature gradient in the tissue by means of conductive heat transfer with the tissue, and cooling means in operative combination with the thermal mass for cooling the thermal mass.
Also provided is an infrared sensor means for detecting infrared emissions emanating from the tissue as the transient temperature gradient progresses into the tissue, and for providing output signals proportional to the detected infrared emissions. Data capture means is provided for sampling the output signals received from the infrared sensor means as the transient temperature gradient progresses into the tissue.
The invention of U.S. Ser. No. 08/820,378 also provides a method for the non-invasive generation and capture of thermal gradient spectra from living tissue. The method comprises the steps of:
In one preferred embodiment taught in Ser. No. 08/816,723 a germanium cylinder, cooled to 0.degree. C., is brought into intermittent contact with the patient's warm skin, and the resulting thermal gradients so formed are used to perform the methodology taught in Ser. No. 081820,378. Skin warming, according to this invention, may be accomplished by simply allowing the patient's skin to naturally re-warm between cooling contact. Alternatively, an external heat source in the form of a second, warmer germanium cylinder may be utilized to facilitate skin warming. The intermittent heating and cooling of the patient's skin results in the creation of transient thermal gradients. In this manner, useful spectra are generated which in turn yield very good measurements of the patient's blood glucose levels.
While the methodology taught in the incorporated references presents a significant advance in non-invasive glucose metrology, there exists room for further improvements.
One such improvement lies in the manner in which the data collected by the apparatus are manipulated. In the methodology taught in Ser. No. 08/820,378 a volts-to-watts radiometric calibration step is often required. To preclude this requirement, a U.S. Patent Application, identified by LaRiviere, Grubman & Payne Docket No. P826 is filed contemporaneously herewith, and is herewith incorporated by reference. The methodology taught therein takes advantage of the fact that by inducing a temperature gradient, a difference parameter between the signal at a reference wavelength and the signal of an analyte absorption wavelength may be detected. The frequency or magnitude or phase difference of this parameter may be used to determine analyte concentration. A further object of the invention taught therein is to provide a method of inducing intermittent temperature modulation and using the frequency, magnitude, or phase differences caused by analyte absorbance to determine analyte concentration. This intermittent temperature may be periodic or aperiodic.
One improvement to the apparatus taught in Ser. No. 08/816,723 enables the methodology taught in LaRiviere, Grubman & Payne Docket No. P826 to be performed. To enable this latter methodology, a fairly rapid series of measurements is taken. While the non-solid-state apparatus taught in Ser. No. 08/816,723 is capable of cycle frequencies of 2 Hz, an apparatus which seeks to implement measurements based on phase differences can, with good effect, make use of much faster cycle frequencies. Faster cycle times equate to faster measurements, and less patient waiting time. An apparatus which enables faster repetitive measurements or cycle times will accordingly enable these advantages.
An additional advantage of the method taught in P826 is that by using a periodically modulated temperature gradient, surface skin effects may be measured and corrected for. Another improvement lies in the nature of the contact between the germanium cylinder and the patient's skin. It is possible that some apparatus performing subsurface thermal gradient spectrometry may require more than one measurement cycle, or "thump". Where this requirement exists in an apparatus requiring intermittent contact between the patient's skin and heat transfer cylinder, one possible source of error exists in the nature of this contact. If several measurement cycles are required to effect an accurate measurement of blood glucose, it follows that the cylinder must be brought into contact with the skin several times. The problem is that each of such contacts tends to be slightly different. Slight differences in pressure at the skin/cylinder interface occur. The patient may move that portion of his or her body, for instance the arm, in contact with the apparatus. Muscular tension may change from reading to reading. Each of these factors, and perhaps others as well, tend to complicate the already complex nature of the contact between the skin and the cylinder. A significant improvement will result if these "rheological effects" can be controlled or standardized if not altogether eliminated.
Closely related to the Theological effect problems previously enumerated is the intermittent nature of the thermal/mechanical/optical interfaces occasioned by the intermittent nature of several of the thermal, mechanical, and optical elements of the apparatus taught in Ser. No. 08/816,723.
Yet another improvement could be made to the apparatus taught in Ser. No. 08/816,723, which relates to a methodology which would perform at least one of the previously discussed subsurface thermal gradient spectrometric methodologies, and which could be reliably performed on an apparatus having no moving parts whereby the thermal gradient is generated and captured.
From the foregoing, advances in the field of non-invasive analyte determinations may be had by an apparatus which supports the methodology taught in the concurrently filed application identified by LaRiviere, Grubman & Payne Docket No. P826, as well as other subsurface thermal gradient spectrometric methodologies including but not necessarily limited to those discussed in U.S. patent application Ser. Nos. 08/820,378 and 08/816,723. An apparatus which enabled more rapid measurement cycle times would not only do much to support the new methodology, but would lessen patient waiting time and improve measurement accuracy. One possible methodology which could provide such advantages would be to form a measuring device which does not rely on a mechanically intermittent device, such as the one taught in U.S. patent application Ser. No. 08/816,723 but which generates transient thermal gradients in a "solid state" manner: i.e., without the mechanical moving of a cooling/measuring cylinder into and out of contact with the patient's skin. Such a solid state device would present the further advantages of leaving intact the thermal, mechanical, and optical interfaces intact, minimizing the rheological effects of intermittent cylinder/skin contact.
Such a system, however, poses a very difficult problem: If the device is left in intimate contact with the patient's skin, it naturally follows that the same element will be used to both cool the skin and to take readings from it. Moreover, to increase cycle times, it may be necessary to provide an external warming to the skin. From this it follows that the same structure will be required to alternately warm the skin, cool the skin, and measure the thermal gradient so induced. Given that the element must perform each of these functions, the cool cylinder must be protected from unwanted warming. The warming function must be performed accurately without undue influence from the cooling function. Finally, could either be performed while measuring the transient thermal gradients so generated?